Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:10]([C:28](=[O:34])[C:29]([O:31]CC)=[O:30])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[C:10]([C:28](=[O:34])[C:29]([OH:31])=[O:30])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(OC(F)(F)F)cc3)cccc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1cn(Cc2ccccc2)c2c(-c3ccc(OC(F)(F)F)cc3)cccc12
Yield: 57.2 %

Procedure:
{1-Benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid was prepared from ethyl {1-benzyl-7-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetate (0.318 g, 0.680 mmol), and potassium hydroxide (0.123 g, 2.19 mmol) in THF (3 mL) and water (3 mL) according to the procedure described in Step 4 of Example 5. Purification by crystallization from isopropanol and drying for 12 hours at 80° C. yielded the title compound as a white solid (0.171 g, 57%), mp: 177-178° C. Mass spectrum (−ESI, [M−H]−) m/z 438; 1HNMR (500 MHz, DMSO-d6): δ 13.8-14.2 (br s, 1H), 8.65 (s, 1H), 8.35 (dd, 1H, J=7.9 Hz and 1.1 Hz), 7.35 (t, 1H, J=7.6 Hz), 7.2-7.25 (m, 4H), 7.1 (t, 1H, J=7.3 Hz), 7.0-7.05 (m, 3H), 6.25 (d, 2H, J=7.3 Hz), and 5.6 ppm (s, 2H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(NCc2ccccc2)c1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A solution of benzylamine (0.77 mL, 7.0 mmol), ethyl 3-fluoro-4-nitrobenzoate (1.0 g, 4.7 mmol) and TEA (2 mL) was heated in DMF (10 mL) for 18 hr at 70° C. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed with H2O (2×100 mL) then 1N HCl (2×100 mL). The organic layer was dried (MgSO4), filtered and then concentrated to provide 1.52 g (˜100%) of crude ethyl 3-(benzylamino)-4-nitrobenzoate as an orange solid. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[NH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:33]([N:19]1[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=2[C:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:18]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: Clc1ccc(N2CCN(CCCc3c[nH]c4c3CCCC4)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)n1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)c2c1CCCC2

Procedure:
3-(3-(4-(4-Chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole (0.5 g) obtained in Example 161 and triethylamine (0.6 ml) were dissolved in dichloromethane (10 ml) and acetyl chloride (0.3 g) was added under ice-cooling with stirring. The reaction mixture was stirred for 2 hours at room temperature and an aqueous potassium carbonate solution is added, and the chloroform layer was separated. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give 1-acetyl-3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[CH:35]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[CH:37][C:36]=1[CH:45]=O.O>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:45][C:36]2[CH:37]=[CH:38][C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:35]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: Fc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(C=Cc2ccc3ccccc3c2)c1
Temperature: -30 °C
Yield: 83.9 %

Procedure:
In the step, 35.00 g (77.55 mmol) of (3-fluorobenzyl)triphenylphosphonium bromide was suspended in 150 ml of THF, and the suspension was cooled to −30° C. and added with 10.25 g (=88.61 mmols) of potassium t-butoxide under stirring. After the addition was finished, the reaction solution was stirred at the same temperature for 1 hour, a 50 ml THF solution of 8.65 g (=55.38 mmol) of 2-naphthoaldehyde was dropped into the same, and then the mixture was slowly heated to room temperature. After being stirred for 18 hours, the reaction mixture was added into iced water, and the mixture was extracted thrice with toluene. The extract was washed thrice with water and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 43.34 g was purified with silica gel chromatography using heptane as the eluent to obtain 11.54 g of 2-[2-(3-fluorophenyl)vinyl]naphthalene as a white solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH:30]OS([O-])=O.[K+].[OH2:36]>CC(C)=O>[CH3:1][S:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:30])=[O:36]
Reactant: CSCc1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cn2)cc1
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)OC(=O)N1CCC(COc2ccc(-c3ccc(CS(C)(=O)=O)cc3)nc2)CC1

Procedure:
The title compound (26 mg, 78%) was prepared as a white solid from 1-methylethyl 4-{[(6-{4-[(methylthio)methyl]phenyl}-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate (31 mg, 0.07 mmol) and Oxone® (0.19 g, 0.3 mmol) in acetone (4 mL) and water (1.5 mL) in a manner similar to Example 81, Step 4. The crude product was triturated with hot hexane containing 1% of MeOH to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.37 (d, 1H, J=2.7 Hz), 7.97 (d, 2H, J=8.1 Hz), 7.67 (d, 1H, J=8.8 Hz), 7.49 (d, 2H, J=8.3 Hz), 7.30-7.20 (m, 1H), 4.92 (septet, 1H, J=6.2 Hz), 4.29 (s, 2H), 4.22 (bs, 2H), 3.90 (d, 2H, J=6.3 Hz), 2.85-2.70 (m, 5H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.40-1.20 (m, 8H); LRMS (ESI), m/z 447 (M+H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:21][O:22][C:23]1[C:24](=[O:51])[C:25]([CH3:50])=[C:26]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:42][CH2:43][C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)=[C:37]([CH:41]=2)[C:38](O)=[O:39])[C:27](=[O:31])[C:28]=1[O:29][CH3:30]>C(Cl)Cl>[CH:1]1([NH:4][C:38](=[O:39])[C:37]2[CH:41]=[C:33]([CH2:32][C:26]3[C:27](=[O:31])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[C:24](=[O:51])[C:25]=3[CH3:50])[CH:34]=[CH:35][C:36]=2[O:42][CH2:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)[CH2:3][CH2:2]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)O)c2)=C(C)C1=O
Reactant: NC1CC1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3cccnc3)c(C(=O)NC3CC3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 12.5 %

Procedure:
Cyclopropylamine (0.0857 g, 1.500 mmol), triethylamine (0.152 g, 1.500 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.254 g, 1.500 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-pyridylmethyloxy)benzoic acid (0.2115 g, 0.500 mmol) and the resulting solution was stirred at room temperature for 13 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.029 g, 0.0627 mmol, 13%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([Cl:22])[N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:19]2[CH:18]=[C:17]([Cl:22])[N:16]=[C:15]([NH2:14])[N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
1-Benzyl-piperazine (5.86 g, 33.3 mmol), 2-amino-4,6-dichloro-pyrimidine (5.46 g, 33.3 mmol) and Cs2CO3 (10.8 g, 36.6 mmol) were combined in anhydrous N,N-dimethylformamide (DMF) (50 mL) and stirred at 90° C. in dry atmosphere for 5 h. The DMF was removed in vacuo, the residue was dissolved in acetone, and 4-(4-Benzyl-piperazin-1-yl)-6-chloro-pyrimidin-2-ylamine (8.5 g, 86%) was is crystallized form acetone.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[CH:15]/[CH:16]=[CH:17]/[CH:18]=[O:19])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:20]([O:26][CH3:27])(=[O:25])[CH2:21][C:22]([CH3:24])=[O:23]>>[CH:11]1[C:12]2[C:13](=[CH:15]/[CH:16]=[CH:17]/[CH:18]([OH:19])[CH2:24][C:22](=[O:23])[CH2:21][C:20]([O:26][CH3:27])=[O:25])[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=C/C=C/C=C1c2ccccc2Sc2ccccc21
Product: COC(=O)CC(=O)CC(O)/C=C/C=C1c2ccccc2Sc2ccccc21

Procedure:
By the method of Example 1, (E)-4-(thioxanthen-9-ylidene)-2-butenal (1.94 g, 7.34 mmol) was reacted with methyl acetoacetate to form present title product, 1.43 g.
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([O:13][C:14]2[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][CH:19]=2)=[C:8]([F:24])[CH:7]=1)[NH2:2].FC(F)(F)C([O-])=O.[CH:33]([CH:35]([CH2:40][C:41]1[CH:42]=[N:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=1)[C:36](OC)=O)=[O:34].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[F:12][C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([F:24])[C:9]=1[O:13][C:14]1[CH:19]=[N:18][C:17]([C:20]([F:21])([F:22])[F:23])=[N:16][CH:15]=1)[CH2:5][CH2:4][O:3][C:1]1[NH:2][CH:36]=[C:35]([CH2:40][C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[N:45][CH:46]=2)[C:33](=[O:34])[N:25]=1
Reactant: COC(=O)C(C=O)Cc1cnc(OC)nc1
Reactant: N=C(N)OCCc1cc(F)c(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Agent: O=C([O-])C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3cc(F)c(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)cn1
Temperature: 80 °C
Yield: 28.8 %

Procedure:
To the solution of 3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethyl carbamimidate, trifluoroacetate (200 mg, 0.421 mmol) and methyl 2-formyl-3-(2-methoxypyrimidin-5-yl)propanoate (113 mg, 0.505 mmol) in 1,4-dioxane (2 mL) was added K2CO3 (233 mg, 1.683 mmol). The mixture was heated with a microwave reactor at 80° C. for 0.5 h. Purification via MDAP then afforded the title compound (65 mg, 28.8% yield). LCMS: rt=3.05 min, [M+H+]=537
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:14]=3)[N:6]2[N:5]=1)=O.[N:23]1([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>COCCO>[CH3:22][S:19]([C:15]1[CH:14]=[C:13]([C:12]2[N:6]3[C:7]([CH:8]=[N:9][C:4]([NH:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:30]=4)=[N:5]3)=[CH:10][CH:11]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:21])=[O:20]
Reactant: Nc1cccc(N2CCOCC2)c1
Reactant: CS(=O)c1ncc2ccc(-c3cccc(S(C)(=O)=O)c3)n2n1
Solvent: COCCO
Product: CS(=O)(=O)c1cccc(-c2ccc3cnc(Nc4cccc(N5CCOCC5)c4)nn23)c1
Yield: 29.8 %

Procedure:
2-Methanesulfinyl-7-(3-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0003727 mol) and 3-Morpholin-4-yl-phenylamine (183 mg, 0.00103 mol) were dissolved in 2-Methoxyethanol (3.2 mL) and the reaction was microwaved at 300 W at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to provide 50.00 mg of [7-(3-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-morpholin-4-yl-phenyl)-amine as a lyophilated powder. (M+H)=450.15. 1H NMR (400 MHz, DMSO, d6) δ 9.40 (s, 1H), 9.04 (s, 1H), 8.51 (m, 2H), 7.95 (d, 1H, J=7.88 Hz), 7.80 (d, 1H, J=8.05 Hz), 7.34 (d, 1H, J=8.09 Hz), 7.26 (d, 1H, J=4.72 Hz), 7.22 (m, 2H), 6.99 (d, 1H, J=4.72 Hz), 6.61 (m, 1H), 3.68 (m, 4H), 3.28 (s, 3H), 2.99 (m, 4H).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27]>ClCCl>[N:21]1([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([N:28]2[CH2:29][CH2:30][CH2:27][CH2:26]2)=[O:13])=[O:19])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CCN(CC)CC
Reactant: C1CCNC1
Solvent: ClCCl
Product: O=C(c1ccccc1SSc1ccccc1C(=O)N1CCCC1)N1CCCC1
Yield: 60.6 %

Procedure:
This compound was prepared according to the general method of Example 112 using 2,2'-dithiobisbenzoyl chloride (1.0 g, 3.0 mmol) in 15 mL of dichloromethane and pyrrolidine (0.63 mL, 7.5 mmol) and triethylamine (1.2 mL, 9 mmol) in 20 mL of dichloromethane, to give 0.75 g of the title compound as a foam, mp 62°-63° C.;
Reaction SMILES: [O:1]1C=C[CH2:3][CH:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.BrBr.[NH2:18][C:19]1[N:24]=[C:23]([NH2:25])[CH:22]=[C:21](O)[N:20]=1.[C:27]([O-:30])(=O)[CH3:28].[Na+]>C(#N)C.O>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:8]=[CH:7][C:6]([CH:2]([OH:1])[CH2:3][N:25]2[C:28]3[C:27]([OH:30])=[N:18][C:19]([NH2:24])=[N:20][C:21]=3[CH:22]=[CH:23]2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(C2CC=CO2)cc1
Reactant: CC(=O)[O-]
Reactant: Nc1cc(O)nc(N)n1
Agent: BrBr
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(C(O)Cn2ccc3nc(N)nc(O)c32)cc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a vigorously stirred mixture of 2.04 g (10 mmol) of methyl 4-(2,3-dihydrofuran-2-yl)benzoate in 15 mL of acetonitrile and 20 mL of water cooled to -10° C. was added dropwise a solution of 1.60 g (10 mmol) of bromine in 5 mL of acetonitrile. The mixture was stirred for 15 min after addition was complete. There was then added 1.26 g (10 mmol) of 2,4-diamino-6-hydroxypyrimidine and 2.46 g (30 mmol) of sodium acetate and the mixture was heated to about 75° C. for 2 h. After about 20 min the product began to precipitate. The mixture was cooled to room temperature and 20 mL of water was added. The product was filtered and dried, affording 2.3 g of crude product. The crude material was purified by slurry in DMF (140° C.), cooling, filtration, and reslurry in ether. Filtration of the ether suspension gave 1.54 g (47%) of the product as a white powder, mp>260° C. 1H NMR (DMSO-d6) δ2.88 (m, 2H), 3.81 (s, 3H), 4.95 (m, 1H), 5.71 (d, J=4.7 Hz, 1H), 6.03 (s, 2H), 6.21 (br d, J=1.8 Hz, 1H), 7.41 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.3 Hz, 2H), 10.28 (s, 1H), 10.64 (br s, 1H); MS(FD) m/z 328 (M+). Anal. Calcd for C16H16N4O4 : C, 58.37; H, 5.04; N, 17.29. Found: C, 58.53; H, 4.91; N, 17.06.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.[I:11]I.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([I:11])=[N:9][NH:10][C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1cc2[nH]nc(I)c2cn1
Temperature: 40 °C
Yield: 58.9 %

Procedure:
A flask was charged with 6-chloro-1H-pyrazolo[4,3-c]pyridine (3 g, 19.54 mmol), iodine (13.11 g, 51.7 mmol), KOH (3.29 g, 58.6 mmol) and DMF (60 mL) (Note: heat generated during adding DMF). The mixture was heated at 40° C. for 16 h and then additional iodine (7.8 g, 30.7 mmol) and KOH (1.6 g, 28.4 mmol) were added. The mixture was heated at 70° C. for 3 h and then quenched with 1N Na2S2O3 and extracted with EtOAc. The organic phase was washed with water, brine and dried (Na2SO4). After evaporation of volatiles DCM was added. A solid precipitated and filtrated off to yield 6-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (3.2 g, 11.51 mmol, 59%), which was carried out in the next step without further purification. MS ESI calc'd. for C6H4ClIN3 [M+1]+ 280, found 280.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12]3[N:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1.[CH3:25]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]([CH3:25])[C:12]3[N:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH:24]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=Nc1cccnc1N2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1c2ccc(Cl)cc2C(c2ccccc2)=Nc2cccnc21
Temperature: 60 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a stirred suspension of 0.25 g (0.01 mole) of sodium hydride (in mineral oil) in 15 ml of anhydrous dimethylformamide was added, portionwise, 3.05 g (0.01 mole) of 8-chloro-6-phenyl-11H-pyrido[2,3-b][1,4]benzodiazepine. The mixture was warmed at about 60° C. for one hr. A solution of 1.42 g (0.01 mole) of methyl iodide in 10 ml of anhydrous dimethylformamide was added dropwise over a 0.5 hr period and the reaction mixture stirred overnight at room temperature after which it was poured into 400 ml of water and stirred for 2 hr. The precipitated solid was recrystallized twice from isopropyl alcohol to give 2.0 g of product, m.p. 153°-6° C. Drying conditions prior to analyses were 1 hr at 82° C./0.1 mm Hg.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[O:28][CH3:29])=[O:16])=[C:4](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1>CC(C)=O>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH:8]1[C:4]2[C:3](=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=2)[NH:14][C:15](=[O:16])[N:17]1[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[O:28][CH3:29]
Reactant: COC(=O)/C=C/c1cccc(F)c1NC(=O)Nc1cc(C(F)(F)F)ccc1OC
Solvent: CC(C)=O
Product: COC(=O)CC1c2cccc(F)c2NC(=O)N1c1cc(C(F)(F)F)ccc1OC
Temperature: 56 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
Methyl (2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]-phenyl}acrylate (50 g) is suspended in acetone (1.2 l) and treated with 1,8-diazobicyclo[5.4.0]undec-7-ene (3.7 g). The suspension is warmed to reflux (ca. 56° C.) and stirred for 4 h. The resulting clear solution is filtered warm through kieselguhr (5 g). The kieselguhr is rinsed with warm acetone (100 ml). Subsequently, acetone (550 g) is distilled off. The resulting suspension is cooled to 0° C. in the course of 3 h and stirred. The product is filtered off with suction, washed twice with cold acetone (50 ml) and dried at 45° C. overnight in the vacuum drying oven using entraining nitrogen. A total of 44.5 g of methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate are obtained as a solid, corresponding to 89% of theory.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[N:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1/[CH:14]=[CH:15]/[C:16]([O:18]CC)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH3:8][C:7]1[CH:6]=[C:5]([N:9]2[N:13]=[N:12][CH:11]=[N:10]2)[CH:4]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[CH:15]=[CH:14]2
Reactant: CCOC(=O)/C=C/c1cc(-n2ncnn2)cc(C)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-n2ncnn2)cc2ccc(=O)[nH]c12

Procedure:
5M Hydrochloric acid (20 cm3) was added to trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-2-yl]phenyl)prop-2-enoate (0.45 g) and the mixture was heated on a steam bath for 1 hour. The mixture was then cooled, brought to pH 7 with aqueous sodium carbonate solution, and extracted with dichloromethane:methanol, 20:1 (3×50 cm3). The combined organic extracts were dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl/acetate:methanol, 10:1. Combination and evaporation of the appropriate fractions afforded 8-methyl-6-(tetrazol-2-yl)-2-(1H)-quinolone, 0.25H2O, m.p. 264°-266°, (0.08 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]([C:30](=[O:47])[NH:31][C:32]3[S:33][C:34]4[C:39]([N:40]=3)=[CH:38][CH:37]=[C:36]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[N:35]=4)[CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:25]1([CH2:24][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([S:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)(=[O:16])=[O:15])=[CH:22][CH:21]=2)[C:30]([NH:31][C:32]2[S:33][C:34]3[C:39]([N:40]=2)=[CH:38][CH:37]=[C:36]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)[N:35]=3)=[O:47])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)Nc3nc4ccc(N5CCOCC5)nc4s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nc2ccc(N3CCOCC3)nc2s1)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCNCC2)cc1
Reaction time: 1 h

Procedure:
Title compound G, 4-{4-[2-Cyclopentyl-1-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.26 g, 0.378 mmol) was dissolved in 5 mL DCM and 2 mL of TFA was added. The solution was stirred for 1 h and then evaporated to afford a crude oil. The residue was partitioned between 2N NaOH and ethyl acetate and extracted numerous times with ethyl acetate, dried over MgSO4, filtered and concentrated to afford a green solid. This material was taken on crude to the next reaction. 1H NMR (400 MHz, DMSO) δ 1.07-1.16 (M, 2H) 1.39-1.50 (m, 2H) 1.52-1.63 (m, 3H) 1.68-1.79 (m, 3H) 2.16 (m, 1H) 2.71 (d, J=4.80 Hz, 4H) 2.76 (d, J=5.05 Hz, 4H) 3.43-3.51 (m, 4H) 3.67-3.74 (m, 4H) 4.07 (d, J=8.84 Hz, 1H) 6.97 (d, J=9.09 Hz, 1H) 7.64-7.69 (m, 2H) 7.69-7.73 (m, 2H) 7.88 (d, J=9.09 Hz, 1H) MS 585.31 [M+1]+.